Cerium is a silvery metallic element, belonging to the lanthanide group. Cerium oxide (Ce2O3/CeO2) is used in precision polishing and lapping applications. Ultra fine nano-size cerium oxide, less than 10 nanometers, is more efficient for coating purposes. Recently, it was reported by B. Rzigalinski et al. that nanoparticles prolong the life of cortical neurons in culture 4 fold over the cells without treatment, decrease the intracellular Ca2+ concentration and prevent UV damage of cortical neurons. See B. Rzigalinski et al., “Cerium Oxide Nanoparticles Extend Cell Longevity and Act as Free Radical Scavengers” at website http://www.med.miami.edu/mnbws/Rzigalinski112.html. Based on its chemical characteristics, this effect is partially due to a decrease of reactive oxygen species (ROS).
Various investigators have shown that nanoceria particles possess antioxidant properties and have demonstrated the survival of neuron cells in cultures against oxidative stress and radiation.
However, the synthetic procedures for nanoceria reported so far are not likely to be approved by the U.S. Food and Drug Administration (FDA) because the synthesis procedures involve the use of surfactants and other toxic materials.
In addition, the published synthetic methods result in uncoated nanoparticles that are not stable and tend agglomerate in aqueous solutions.
Further developments in biomedical research reveal the efficacy of coated magnetic nanoscale particle compositions for therapeutic uses. In Patent Publication WO/2003/005029 to Zhenghe Xu et al. iron and iron oxide particles are coated with dextran for biological cell separation using magnetic carrier technology. The dextran coating is used to prevent mechanical instability of the particle in suspension.
U.S. Patent Publication 2003/0124,194 to Gaw et al. discloses amine functionalized superparamagnetic nanoparticles using a process that consists of coating the magnetic nanoparticles with a carboxylated polymer then subsequently reacting the carboxylated functionalized magnetic nanoparticles with carbodiimide and a large excess of diamine, after which the amine-terminated nanopartices are reacted with bifunctional crosslinking agents and various biomolecules.
U.S. Patent Publication 2005/0130167 to Gang Boa, et al. provides multifunctional magnetic nanoparticle probe compositions for molecular imaging and monitoring wherein the magnetic nanoparticle has a biocompatible coating, such as, dextran, thereon.
U.S. Patent Publication 2006/0014938 to Groman et al. describes stable aqueous colloidal lanthanide oxides, including cerium oxide, some of which are associated with a polymer, including dextran. The colloidal compositions are useful as imaging agents in technology requiring injectable chemicals for contrast agents. There is no mention of cerium oxide coated with polymers having autocatalytic and antioxidant properties.
U.S. Patent Publication 2006/0142749 to Robert Ivkov discloses thermotherapeutic compositons for treating disease. The thermotherapeutic compositions include magnetic nanoparticles that may be coated to enhance the heating properties of a bioprobe, particularly if the coating is a polymeric material that can include dextran.
Thus, polymeric coatings including dextran have been reported for use on magnetic nanoparticles and the results seem promising in molecular imaging, monitoring and therapeutic treatment of disease.
In addition, prior to the present invention, most synthetic procedures for nanoceria resulted in nanoparticles with poor water solubility and provided ceria particles that precipitate from aqueous solutions. Also, prior art synthetic procedures involve the use of toxic solvents, therefore hindering their potential clinical use.
It is desirable to find reliable solutions to use of nanoceria particles with antioxidant properties in the treatment of many human diseases that are due to the death of cells in specific tissues or organs. The majority of those diseases are due to accumulation of metabolic insults from reactive oxygen species originating within or outside of the cells. These diseases include all forms of blindness whether hereditary, light-induced, or physical damage such as occurs in retinal detachment. In addition, damage due to ageing, stroke, cardiac infarction, burns, etc, which proceed through reactive oxygen species, can be addressed with the nanoceria particles synthesized according the present invention.
The ability of nanoceria particles to reversibly switch from Ce+3 to Ce+4 is a key factor in their use in catalytic and biological applications as antioxidants. In co-pending U.S. application Ser. No. 11/965,343 filed on Dec. 27, 2007, it was reported that the polymeric coating does not affect the autocatalytic properties of nanoceria, as hydrogen peroxide and peroxyl radicals can diffuse through the hydrophilic polymer coating and oxidize Ce+3 to Ce+4. Thus, polymer-coated nanoceria particles are used as antioxidants in biomedical applications, such as, protection against radiation damage, oxidative stress and inflammation.
The present application shows that polymer-coated nanoceria particles with enhanced biocompatibility and stability in aqueous solution exhibit a pH-dependent antioxidant activity and provide a means for tailoring reversible and non-reversible antioxidant properties of polymer-coated nanoceria particles.